Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gpIIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111. Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. See U.S. Pat. Nos. 4,578,079 and 4,614,517.
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Haverstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 491-497 (1987). Still other such inhibitory peptides are disclosed in EP Patent Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR2## wherein x=6 to 10,
y=0 to 4, PA1 Z=H, COOH, CONH.sub.2 OR C.sub.1-6 alkyl, PA1 Ar=phenyl, biphenyl or naphthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridyl or thienyl group, and PA1 Asp=aspartic acid residue. PA1 R.sub.2 represents a lower alkyl, lower alkenyl, lower alkynyl or benzyl group, or a lower alkoxycarbonylalkyl, lower carboxyalkyl, or lower hydroxyalkyl group; PA1 R.sub.3 and R.sub.4 identical or different, each represents a lower alkyl or lower hydroxyalkyl radical, lower alkenyl or lower alkynyl radical or form together with the nitrogen to which they are attached, a saturated heterocycle such as morpholino, thiomorpholino, pyrrolidino not substituted or substituted by an alkoxycarbonyl or carboxy group, piperazino, 4-(lower alkyl)piperazino, 4-(lower hydroxyalkyl)piperazino, or piperidino not substituted or substituted by one of the following groups: lower alkyl, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl, hydroxyamino, alkoxycarbonyl or carboxy. PA1 Ar represents a phenyl, alpha-naphthyl or beta-naphthyl group, possibly substituted, or a heteroaryl group chosen from the radicals pyridyl, quinolinyl, or isoquinolinyl, possibly substituted, as well as their isomers and their mixtures and their salts with pharmaceutically acceptable mineral or organic acids PA1 R.sub.2 and R.sub.3 identical or different, each represents a lower alkyl or hydroxyalkyl, lower alkenyl or lower alkynyl radical, or they form together with the nitrogen to which they are attached, a saturated heterocycle such as morpholino, thiomorpholino, pyrrolidino unsubstituted or substituted by an alkoxycarbonyl or carboxyl group, piperazino, 4-(lower alkyl)-piperazino or piperidino unsubstituted or substituted by a lower alkyl, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl, alkoxycarbonyl or carboxyl group. PA1 Ar represents a phenyl, a possibly substituted alpha-naphthyl or beta-naphthyl group, or else a heteroaryl group chosen from pyridyl, quinolinyl, isoquinolinyl, possibly substituted PA1 Q.sup.1 stands for hydrogen, methyl or phenyl, PA1 Q.sup.2 stands for hydrogen, phenyl-low-alkyl or low alkyl that can be cleaved under physiological conditions, PA1 X stands for 1,4-phenylene, 2,5- or 3,6-pyridylene or, 1,4-piperidinylene, which is bonded to group Y through the C atom in the 4-position, PA1 Y is a group having the formula EQU --(CH.sub.2).sub.0-2 --CONHCH(Q.sup.3)(CH.sub.2).sub.1-3 (Y.sup.1) EQU --CONHCH.sub.3 CH(Q.sup.4) (Y.sup.2) EQU --(CH.sub.2).sub.3 NHCOCH.sub.2 -- (Y.sup.3) EQU --NHCO(CH.sub.2).sub.3 -- (Y.sup.4) ##STR6## where Q.sup.3 stands for hydrogen, methyl, phenyl, --COOH, --COO-- low-alkyl, --CONH(CH.sub.2).sub.2 --COOH or --CONH(CH.sub.2).sub.2 --COO-low-alkyl, PA1 Q.sup.4 hydrogen, methyl or phenyl, PA1 Z a 1,4-piperazinylene group, a 1,4-piperazinylene group which is bonded to the CO group through the N atom in the 1-position or a group having the formula EQU --NHCH(R.sup.1)-- or --NHCH(COR.sup.2)-- PA1 R.sup.1 stands for hydrogen, methyl, phenyl or a --COO-low-alkyl, PA1 R.sup.2 stands for the residue of an .alpha.-aminocarboxylic acid bonded through the amino group or of an ester or amide thereof, or a group having the formula --NHCH.sub.2 CH.sub.2 --Ar, or --CO-R.sup.2, or, if applicable, a mono- or di-low-alkylated carbamoyl group or a pyrrolidinoyl or piperidinoyl group, PA1 Ar stands for a phenyl or a phenyl substituted by low alkyl, low alkoxy, --COOH, --COO-low-alkyl, --O(CH.sub.2).sub.1-4 --COOH, --O(CH.sub.2).sub.1-4 --COO-low-alkyl, --CONH.sub.2, --CONH-low-alkyl, --CON(low alkyl).sub.2, pyrrolidinoyl or piperidinoyl which are said to have inhibitory action on the bonding of adhesive proteins to blood platelets as well as blood platelet aggregation and cell-cell adhesion. These compounds are structurally distinct from the present invention because they have an additional --NHCH(R.sup.1) or --NHCH(COR.sup.2)-- or a piperazinylene group at the "Z" position of Formula A. An additional --NHCH(R.sup.1) or an additional --NHCH(COR.sup.2) or a piperazinylene group is not present in the instant invention. PA1 R.sub.2 is hydrido; alkyl having 1 to 6 carbon atoms; phenyl; phenylalkyl wherein the alkyl is 1 to 6 carbon atoms and wherein the phenyl ring may be independently substituted one or more times by a substituent selected from alkyl having 1 to 6 carbon atoms, halo, and alkoxy having 1 to 6 carbon atoms; PA1 R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrido, alkyl having 1 to 6 carbon atoms, hydroxy, alkoxy having 1 to 6 carbon atoms and halo; PA1 W is hydrido or alkyl having 1 to 6 carbon atoms; PA1 Y is alkyl having 1 to 6 carbon atoms wherein said alkyl may be substituted one or more times by a substituent independently selected from alkyl having 1 to 6 carbon atoms, hydroxy and oxo; alkenyl having 2 to 6 carbon atoms; alkynyl having 2 to 6 carbon atoms or alkylcarbonylaminoalkyl wherein the alkyl has 1 to 6 carbon atoms and wherein the amino may be further substituted by alkyl having 1 to 4 carbon atoms; PA1 Z is hydrido, carboxyl, alkoxycarbonyl having 1 to 6 carbon atoms or alkylcarboxyl having 1 to 6 carbon atoms; and PA1 m is an integer from 0 to 4. PA1 R.sub.2 is hydrido or alkyl having 1 to 6 carbon atoms; PA1 R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrido, alkyl having 1 to 6 carbon atoms, hydroxy, alkoxy having 1 to 6 carbon atoms and halo; PA1 W is hydrido or alkyl having 1 to 6 carbon atoms; PA1 Y is alkyl having 1 to 6 carbon atoms wherein said alkyl may be substituted one or more times by a substituent independently selected from alkyl having 1 to 6 carbon atoms, hydroxy and oxo; alkenyl having 2 to 6 carbon atoms or alkynyl having 2 to 6 carbon atoms; PA1 Z is hydrido, carboxyl or alkoxycarbonyl having 1 to 6 carbon atoms; and PA1 m is an integer from 0 to 4. PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine, dimethyl ester; PA1 N-[N-[5-[4-(aminoiminomethyl]phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine, diethyl ester; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine acetate; PA1 N-[N-[5-[3-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxo-4-pentynyl]-L-.alpha.-aspartyl]- L-phenylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxo-4E-pentenyl]-L-.alpha.-aspartyl] -L-phenylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxo-4Z-pentenyl]-L-.alpha.-aspartyl] -L-phenylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-N-met hyl-L-phenylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1,4-dioxopentyl]-L-.alpha.-aspartyl]-L -phenylalanine; PA1 N-[N-[6-[4-(aminoiminomethyl)phenyl]-1-oxohexyl]-L-.alpha.-aspartyl]-L-phen ylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-4-hydroxy-1-oxopentyl]-L-.alpha.-aspar tyl]-L-phenylalanine; PA1 N-[N-[6-[3-(aminoiminomethyl)phenyl]-1-oxo-5Z-hexenyl]-L-.alpha.-aspartyl]- L-phenylalanine; PA1 N-[N-[4-[4-(aminoiminomethyl)phenyl]-1-oxobutyl]-L-.alpha.-aspartyl]-L-phen ylalanine; PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-phe nylalanine, monohydrochloride; PA1 3S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-oxo-4-[(2-phenylet hyl)amino]butanoic acid, acetate; PA1 3S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[[2-(4-methoxyphen yl)ethyl]amino]-4-oxobutanoic acid; and PA1 N-[N-[6-[4-(aminoiminomethyl)phenyl]-1-oxohexyl]-L-.alpha.-aspartyl]-L-phen ylalanine. PA1 R.sub.2 is hydrido or alkyl having 1 to 6 carbon atoms; PA1 R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrido, alkyl having 1 to 6 carbon atoms, hydroxy, alkoxy having 1 to 6 carbon atoms and halo; PA1 W is hydrido or alkyl having 1 to 6 carbon atoms; PA1 Y is alkyl having 1 to 6 carbon atoms wherein said alkyl may be substituted one or more times by a substituent independently selected from alkyl having 1 to 6 carbon atoms, hydroxy and oxo; alkenyl having 2 to 6 carbon atoms or alkynyl having 2 to 6 carbon atoms; PA1 Z is hydrido, carboxyl or alkoxycarbonyl having 1 to 6 carbon atoms; and PA1 m is an integer from 0 to 4. PA1 3S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(2-methylpropyl)a mino]-4-oxobutanoic acid; and PA1 N-[N-[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]-L-.alpha.-aspartyl]-L-val ine PA1 R.sub.2 is hydrido; alkyl having 1 to 6 carbon atoms; phenyl; phenylalkyl wherein the alkyl is 1 to 6 carbon atoms and wherein the phenyl ring may be independently substituted one or more times by a substituent selected from alkyl having 1 to 6 carbon atoms, halo, and alkoxy having 1 to 6 carbon atoms; PA1 R.sub.3 and R.sub.4 are each independently selected from the group consisting of hydrido, alkyl having 1 to 6 carbon atoms, hydroxy, alkoxy having 1 to 6 carbon atoms and halo; PA1 W is hydrido or alkyl having 1 to 6 carbon atoms; PA1 Y is alkyl having 1 to 6 carbon atoms wherein said alkyl may be substituted one or more times by a substituent independently selected from alkyl having 1 to 6 carbon atoms, hydroxy and oxo; alkenyl having 2 to 6 carbon atoms or alkynyl having 2 to 6 carbon atoms; PA1 Z is hydrido, carboxyl or alkoxycarbonyl having 1 to 6 carbon atoms; and PA1 m is an integer from 0 to 4. PA1 3 S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(2-carboxyethyl)( phenylmethyl)amino]-4-oxobutanoic acid; PA1 3S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(2-carboxyethyl)( 2-phenylethyl)amino]-4-oxobutanoic acid; PA1 3 S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(2-carboxyethyl)[ 2-(4-methoxyphenyl)ethyl]amino]-4-oxobutanoic acid; and PA1 3 S-[[5-[4-(aminoiminomethyl)phenyl]-1-oxopentyl]amino]-4-[(2-carboxyethyl)( 2-methylpropyl)amino]-4-oxobutanoic acid.
U.S. Pat. No. 4,977,168 discloses compounds having the following structural formula ##STR3## wherein R.sub.1 represents hydrogen, a lower alkyl group, a lower hydroxyalkyl group, a benzyl group, a phenyl group or a 4-hydroxyphenyl group;
which are useful as antithrombotic agents. These compounds are structural distinct from the present invention because they are arylsulphonylaminoacyl aminophenylalaninamide derivatives in contrast to the compounds of the present invention which are alkanoic acid/esters-1-amidinophenylalkyl carbonylamino derivatives.
U.S. Pat. No. 4,791,102 discloses compounds having the following structural formula ##STR4## wherein R.sub.1 represents a lower alkyl, lower hydroxyalkyl, or benzyl group, a phenyl or a 4-hydroxyphenyl group.
which are useful as selective inhibiting agents of thrombin and antithrombotics. These compounds are structural distinct from the present invention because they are arylsulphonylaminoacylaminophenyl alaninamides in contrast to the compounds of the present invention which are alkanoic acid/esters-1-amidinophenylalkylcarbonyl amino derivatives.
European Patent Application 372,486 discloses N-acyl beta amino acid derivatives of the formula: ##STR5## and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
European Patent Application 381 033 A1 discloses amidino or guanidino-aryl substituted alkanoic acid derivatives having the following structural formula EQU R.sup.1 -A-(W).sub.a -X-(CH.sub.2).sub.b -(Y).sub.c -B-Z-COOR
which are useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors. These compounds are structural distinct from the present invention because they are aryl acetic acid/esters 2-amidino/guanidino phenylalkylcarbonyl amino derivatives in contrast to the compounds of the present invention which are alkanoic acid/esters-1-amidinophenylalkylcarbonyl amino derivatives.
European Patent Application 445,796 A2 discloses acetic acid derivatives having the formula EQU H.sub.2 N(NH)C-X-Y-CO-Z-CH(Q.sup.1)COOQ.sup.2 (Formula A)
where
where